Chemokines (chemoattractant cytokines) are a family of homologous serum proteins of between 7 and 16 kDa, which were originally characterized by their ability to induce migration of leukocytes. Most chemokines have four characteristic cysteines (Cys), and depending on the motif displayed by the first two cysteines, they have been classified into CXC or alpha, CC or beta, C or gamma, and CX3C or delta chemokine classes. Two disulfide bonds are formed between the first and third cysteine and between the second and fourth cysteine. In general, it was thought that the disulfide bridges were required, and Clark-Lewis and co-workers reported that, at least for IL-8, the disulfide bridges are critical for chemokine activity (Clark-Lewis et al., J. Biol. Chem. 269:16075–16081, 1994). The only exception to having four cysteines is lymphotactin, which has only two cysteine residues. Thus, lymphotactin manages to retain a functional structure with only one disulfide bond.
In addition, the CXC, or alpha, subfamily has been divided into two groups depending on the presence of the ELR motif (Glu-Leu-Arg) preceding the first cysteine: the ELR-CXC chemokines and the non-ELR-CXC chemokines (see, e.g., Clark-Lewis, supra, and Belperio et al., “CXC Chemokines in Angiogenesis,” J. Leukoc. Biol. 68:1–8, 2000).
ELR-CXC chemokines, such as IL-8, are generally strong neutrophil chemoattractants while non-ELR chemokines, such as IP-10, and SDF-1, predominantly recruit lymphocytes. CC chemokines, such as RANTES, MIP-1-alpha, MCP-1, generally function as chemoattractants for monocytes, basophils, eosinophils, and T-cells but not neutrophils. In general, chemokines are chemotactic agents that recruit leukocytes to the sites of injuries.
Specific Chemokines
IL-8
Interleukin-8 (IL-8 or CXCL8) was first identified in 1987 as a chemokine with the ability to specifically activate neutrophils. Upon exposure to IL-8, neutrophils are activated, and change their shape. Neutrophils are activated by a process that is probably mediated by an increase in intracellular calcium levels. This activation allows neutrophils to migrate across the vascular wall. Secretion of IL-8 can occur from a wide variety of cells, including other leukocytes, fibroblasts, endothelial cells, and epithelial cells in response to ischemia and trauma.
IP-10
Interferon-inducible protein-10 (IP-10 or CXCL10) is induced by interferon-gamma and TNF-alpha, and is produced by keratinocytes, endothelial cells, fibroblasts and monocytes. IP-10 is thought to play a role in recruiting activated T cells to sites of tissue inflammation (Dufour, et al., “IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking,” J Immunol., 168:3195–204, 2002). In addition, IP-10 may play a role in hypersensitivity. It may also play a role in the genesis of inflammatory demyelinating neuropathies (Kieseier, et al., “Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10,” Brain 125:823–34, 2002).
MIP-1α
Macrophage inflammatory protein-1-alpha (MIP-1α, MIP-1-alpha or CCL3) is a factor produced by macrophages in response to their stimulation by bacterial endotoxins. It activates neutrophils, eosinophils, and basophils and appears to play a role in inflammation. Additionally, it is especially potent as a basophil agonist, and appears to act through a rapid rise in intracellular calcium, and causes the release of histamine, sulfido-leukotrienes, and also plays a role in chemotaxis. MIP-1α may also act to inhibit stem cell proliferation.
RANTES
RANTES (Regulated upon Activation, Normal T-cell Expressed, and presumably Secreted or CCL5) is a chemokine that acts on T-cells, eosinophils and basophils and assists in recruiting leukocytes to inflammatory sites. In particular, it increases the adherence of monocytes to endothelial cells, and selectively supports the migration of certain types of leukocytes. In some cases, RANTES has been shown to activate basophils and causes the release of histamines. It may also be involved in the proliferation and activation of certain types of killer cells.
I-309
I-309 refers to the name of a cDNA clone encoding a chemokine (Miller, et al., “A novel polypeptide secreted by activated human T lymphocytes,” J Immunol., 143(9):2907–16, 1989). I-309 is chemotactic for human monocytes, and additionally activates them. However, it appears to have no effect on neutrophils.
MCP-1
Monocyte chemoattractant (or chemotactic) protein-1 (monocyte chemotactic protein-1, MCP-1 or CCL2) is another CCL chemokine. It is expressed by monocytes, endothelial cells, smooth muscle cells, and certain types of epithelial cells in culture. The expression of MCP1 is induced in human peripheral blood mononuclear leukocytes by phytohemagglutinin (PHA), lipopolysaccharide, and IL1. MCP-1 functions as a chemoattractant for monocytes but not neutrophils. There have been reports that two point mutations are sufficient for MCP-1 to become chemotactic for neutrophils. MCP-1 activates monocytes and macrophages in vivo, as well as basophils. Additionally, it can induce the proliferation and activation of certain types of killer cells.
CCL28
CCL28 (hMEC) is a recently described CC chemokine which may play a particularly important role in homeostasis or inflammatory responses in the gastrointestinal system (Wang et al., J. Biol. Chem. 275:22313–23, 2000).
SDF-1
Stromal cell-derived factor-1 (SDF-1 or CXCL12) is a CXC chemokine that demonstrates in vitro activity with respect to lymphocytes and monocytes but not neutrophils. It is a highly potent in vivo chemoattractant for mononuclear cells. SDF-1 has been shown to induce intracellular actin polymerization in lymphocytes, and to induce a transient elevation of cytoplasmic calcium in some cells.
Chemokine Receptors
The receptors for chemokines are G-protein coupled seven-transmembrane receptors. Based on the chemokine class they bind, the receptors have been named CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5 (all of which bind CXC chemokines); CCR1 through CCR9 (all of which bind CC chemokines); XCR1 (which binds the C chemokine, Lptn); and CX3CR1 (which binds the CX3C chemokine, fractalkine or neurotactin (See Table 1)).
The chemokines and their receptors have received increasing attention in the last few years. In addition to their role in HIV pathogenesis, it is now clear that chemokines participate in many pathological conditions such as inflammation and diseases or conditions associated with autoimmune responses. They also play a very important role in normal homeostasis, including lymphoid development and migration, and the growth of bone. As a result of their role in various physiological processes and pathological conditions and diseases, chemokines have important potential therapeutic applications.
TABLE 1Chemokine receptorsHuman chemokine ligandsCXCR1IL-8, GCP-2CXCR2IL-8, GCP-2, Gro α, Gro β, Gro γ, ENA-78, PBPCXCR3MIG, IP-10, I-TACCXCR4SDF-1/PBSFCCR1MIP-1 α, MIP-1 β, RANTES, HCC-1, 2, 3, and 4CCR2MCP-1, MCP-2, MCP-3, MCP-4CCR3Eotaxin-1 eotaxin-2, MCP-3CCR4TARC, MDC, MIP-1 α, RANTESCCR5MIP-1 α, MIP-1 β, RANTESCCR6MIP-3 α/LARCCCR7MIP-3 β/ELC, 6Ckine/LCCCR8I-309CCR9TECKCCR10CCL27, CCL28(hMEC)